Open AccessMyD88‐induced downregulation of IRAK‐4 and its structural requirements
Author(s) -
Hatao Fumihiko,
Yamamoto Maya,
Muroi Masashi,
Kaminishi Michio,
Tanamoto Kenichi
Publication year - 2008
Publication title -
fems immunology & medical microbiology
Language(s) - English
Resource type - Journals
eISSN - 1574-695X
pISSN - 0928-8244
DOI - 10.1111/j.1574-695x.2008.00425.x
Subject(s) - downregulation and upregulation , trif , biology , tlr2 , microbiology and biotechnology , signal transduction , tlr3 , tlr4 , receptor , toll like receptor , innate immune system , gene , biochemistry
IRAK‐4 plays an essential role in Toll‐like receptor (TLR)/IL‐1 receptor signaling. However, its signaling and regulation mechanisms have remained elusive. We have reported previously that stimulation of TLR2, TLR4 or TLR9, but not TLR3, leads to downregulation of IRAK‐4 protein. Here, we show that expression of MyD88 leads to downregulation of endogenous as well as exogenously expressed IRAK‐4 protein in HEK293 cells. Expression of TRIF did not cause IRAK‐4 downregulation although it induced NF‐κB activation. Expression of either a deletion mutant of MyD88 lacking its death domain or MyD88s, neither of which induced NF‐κB activation, did not lead to IRAK‐4 downregulation. MyD88‐induced downregulation was observed in an IRAK‐4 mutant lacking the kinase domain, but not in another mutant lacking the death domain. These results demonstrate that downregulation of IRAK‐4 requires activation of the MyD88‐dependent pathway and that the death domains of both MyD88 and IRAK‐4 are important for this downregulation.